Developing Topics.

BACKGROUND

The interplays between risk factors and apolipoprotein E4 allele (APOE e4) could play crucial roles in influencing dementia occurrence. However, the observational evidence remains fragmented. This study aims to comprehensively evaluate whether the risk factor profile of dementia varied by the presence of APOE e4.

METHOD

A systematic search of PubMed, EMBASE, and the Cochrane Library was conducted up to June 2023. Population-based longitudinal studies were included if they reported associations of modifiable or nonmodifiable risk factors with all-cause dementia (ACD) or Alzheimer's disease (AD) stratified by APOE e4 status. The multivariable-adjusted effects were separately combined using random-effects models in APOE e4 carriers and non-carriers. Meta-regression analyses were performed to test stratification effects by APOE e4. The study protocol was pre-registered in PROSPERO and the registration number is CRD42024612115.

RESULT

A total of 170 eligible literatures with 173 factors were identified, of which 112 with 48 factors were included in the meta-analysis, comprising 1,202,988 APOE e4 carriers and 2,190,941 non-carriers. Meta-regression revealed stratification effects by APOE e4 for nine ACD risk factors. Among these, four factors (nonsteroidal anti-inflammatory drugs, statins, frequent drinking, and high systolic blood pressure) showed significant associations only in APOE ε4 carriers, while five factors (light-to-moderate alcohol consumption, female, physical activity, diabetes mellitus, and loneliness) were significant only in non-carriers. Moreover, the associations for six risk factors (aging, education, hypertension, cardiovascular disease, stroke, and depression) were not modulated by the presence of APOE e4 status. As for AD, meta-regression analyses identified diabetes as a specific risk factor in APOE e4 non-carriers and depression was found a risk factor independent of APOE e4. Subgroup analyses revealed four factors uniquely in APOE e4 carriers (NSAIDs use, vitamin E intake, high SBP, and loneliness) and other six factors specific to non-carriers (aging, female, Mediterranean diet, physical activity, cardiovascular disease, and serum testosterone).

CONCLUSION

APOE e4 could interact with other risk factors to influence dementia occurrence. Future studies are needed to validate these interactions and elucidate the underlying mechanisms, enabling precise prediction and prevention of dementia and AD.

© 2025 The Alzheimer's Association. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.